Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection

作者：Beers Stephen A; French Ruth R; Chan H T Claude; Lim Sean H; Jarrett Timothy C; Vidal Regina Mora; Wijayaweera Sahan S; Dixon Sandra V; Kim Hyungjin; Cox Kerry L; Kerr Jonathan P; Johnston David A; Johnson Peter W M; Verbeek J Sjef; Glennie Martin J; Cragg Mark S^*

来源：Blood, 2010, 115(25): 5191-5201.

DOI：10.1182/blood-2010-01-263533

Rituximab, a monoclonal antibody that targets CD20 on B cells, is now central to the treatment of a variety of malignant and autoimmune disorders. Despite this success, a substantial proportion of B-cell lymphomas are unresponsive or develop resistance, hence more potent anti-CD20 monoclonal antibodies (mAbs) are continuously being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAbs are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B cells, despite both operating exclusively via activatory Fc gamma receptor-expressing macrophages. Much of this disparity in performance is attributable to type I mAb-mediated internalization of CD20 by B cells, leading to reduced macrophage recruitment and the degradation of CD20/mAb complexes, shortening mAb half-life. Importantly, human B cells from healthy donors and most cases of chronic lymphatic leukemia and mantle cell lymphoma, showed rapid CD20 internalization that paralleled that seen in the Tg mouse B cells, whereas most follicular lymphoma and diffuse large B-cell lymphoma cells were far more resistant to CD20 loss. We postulate that differences in CD20 modulation may play a central role in determining the relative efficacy of rituximab in treating these diseases and strengthen the case for focusing on type II anti-CD20 mAb in the clinic. (Blood. 2010;115(25):5191-5201)

• 出版日期2010-6-24